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D Davison

Publications and source records attributed to D Davison.

At least 19 recordsLinked to original sources
PubMed2005

Impact of human immunodeficiency virus type 1 gp41 amino acid substitutions selected during enfuvirtide treatment on gp41 binding and antiviral potency of enfuvirtide in vitro.

Enfuvirtide (ENF), a novel human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, has potent antiviral activity against HIV-1 both in vitro and in vivo. Resistance to ENF observed after in vitro passaging was associated with changes in a three-amino-acid (aa) motif, GIV, at positions 36 to 38 of gp41. Patients with ongoing viral replication while receiving ENF during clinical trials acquired substitutions within gp41 aa 36 to 45 in the first heptad repeat (HR-1) of gp41 in both population-based plasma virus sequences and proviral DNA sequences from isolates showing reduced susceptibilities to ENF. To investigate their impact on ENF susceptibility, substitutions were introduced into a modified pNL4-3 strain by site-directed mutagenesis, and the susceptibilities of mutant viruses and patient-derived isolates to ENF were tested. In general, susceptibility decreases for single substitutions were lower than those for double substitutions, and the levels of ENF resistance seen for clinical isolates were higher than those observed for the site-directed mutant viruses. The mechanism of ENF resistance was explored for a subset of the substitutions by expressing them in the context of a maltose binding protein chimera containing a portion of the gp41 ectodomain and measuring their binding affinity to fluorescein-labeled ENF. Changes in binding affinity for the mutant gp41 fusion proteins correlated with the ENF susceptibilities of viruses containing the same substitutions. The combined results support the key role of gp41 aa 36 to 45 in the development of resistance to ENF and illustrate that additional envelope regions contribute to the ENF susceptibility of fusion inhibitor-naïve viruses and resistance to ENF.

Amino Acid Substitution↗
PubMed2000

Sympathetic activation by sildenafil.

BACKGROUND: Sildenafil citrate is an effective and widely prescribed therapy for erectile dysfunction. Little is known about the effects of sildenafil on neural control of the circulation or about the effects of sildenafil on neurocirculatory stress responses. METHODS AND RESULTS: We studied 14 normal volunteers (age 32+/-7 years) who were randomized in a double-blind crossover fashion to receive a single oral dose of sildenafil 100 mg or placebo on 2 separate study days. Blood pressure, heart rate, forearm vascular resistance, muscle sympathetic nerve activity, and plasma catecholamines were measured at baseline and at 30 and 60 minutes after sildenafil and after placebo administration. The effects of sildenafil and placebo on neural and circulatory responses to stressful stimuli (sustained handgrip, maximal forearm ischemia, mental stress, and the cold pressor test) were also evaluated. Blood pressure, heart rate, and forearm vascular resistance after sildenafil and placebo were similar. However, muscle sympathetic nerve activity increased strikingly after sildenafil (by 141+/-26%, mean+/-SEM) compared with placebo (3+/-8%) (P=0.006); plasma norepinephrine levels also increased by 31+/-5% after sildenafil administration (P=0.004). Sympathetic nerve traffic during mental, physical, and cold stresses was 2- to 8-fold higher after sildenafil than with placebo (P<0.05). CONCLUSIONS: Sildenafil causes a marked increase in sympathetic activation, evident both at rest and during stressful stimuli. Sympathetic activation by sildenafil may have implications for understanding cardiovascular events associated with sildenafil use.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2000

Personality type and neural circulatory control.

Psychosocial factors, including type A personality, anger, hostility, and anxiety, have been implicated in the pathogenesis of cardiovascular disease. Abnormal sympathetic responses to stress may help explain the link between certain behavior patterns and cardiovascular disease. We tested the hypothesis that in normal humans, type A personality characteristics are associated with exaggerated heart rate, pressor, and sympathetic nerve responses to mental and physical stress. We measured heart rate, blood pressure, and muscle sympathetic nerve activity (obtained with direct intraneural recordings) at rest and during stress in 45 healthy subjects (19 men and 26 women, age 29.2+/-8.7 years) who had no chronic diseases and were taking no medications. Subjects were divided into tertiles based on type A scores. There were no significant differences in sympathetic or hemodynamic reactivity among the 3 different intensity levels of type A characteristics. Baseline measures and responses to stress tests were similar across the 3 groups. Sympathetic and hemodynamic changes during stress tests were also similar in subject groups stratified according to anger scale and cynicism scale. Sympathetic nerve and hemodynamic measurements at rest and during stress were not different in normal subjects with type A characteristics. Abnormalities in sympathetic or cardiovascular reactivity are unlikely to be implicated in any excess of cardiovascular disease in people with type A personality characteristics.

Adult↗
PubMed1999

d2_cluster: a validated method for clustering EST and full-length cDNAsequences.

Several efforts are under way to condense single-read expressed sequence tags (ESTs) and full-length transcript data on a large scale by means of clustering or assembly. One goal of these projects is the construction of gene indices where transcripts are partitioned into index classes (or clusters) such that they are put into the same index class if and only if they represent the same gene. Accurate gene indexing facilitates gene expression studies and inexpensive and early partial gene sequence discovery through the assembly of ESTs that are derived from genes that have yet to be positionally cloned or obtained directly through genomic sequencing. We describe d2_cluster, an agglomerative algorithm for rapidly and accurately partitioning transcript databases into index classes by clustering sequences according to minimal linkage or "transitive closure" rules. We then evaluate the relative efficiency of d2_cluster with respect to other clustering tools. UniGene is chosen for comparison because of its high quality and wide acceptance. It is shown that although d2_cluster and UniGene produce results that are between 83% and 90% identical, the joining rate of d2_cluster is between 8% and 20% greater than UniGene. Finally, we present the first published rigorous evaluation of under and over clustering (in other words, of type I and type II errors) of a sequence clustering algorithm, although the existence of highly identical gene paralogs means that care must be taken in the interpretation of the type II error. Upper bounds for these d2_cluster error rates are estimated at 0.4% and 0.8%, respectively. In other words, the sensitivity and selectivity of d2_cluster are estimated to be >99.6% and 99.2%.

Algorithms↗
PubMed1999

The effect of Cys LT1 receptor blockade on airway responses to allergen.

STUDY OBJECTIVE: To evaluate the effect of a potent experimental leukotriene receptor antagonist, MK-571, on airway responses to inhaled allergen. DESIGN: Randomized, double-blind, placebo-controlled, crossover trial. SETTING: Clinical research center. SUBJECTS: Eight male volunteers with allergic asthma. INTERVENTIONS: An intravenous loading dose was followed by an 8-hour infusion of MK-571 or placebo, with a 7- to 14-day washout between treatments. Allergen challenge was performed after the loading dose and a histamine challenge was performed before and 24 hours after allergen. MEASUREMENTS AND MAIN RESULTS: Forced expiratory volume in 1 second was measured serially. MK-571 provided about 50% protection during maximum early and late responses compared with placebo (p=0.005), but airway obstruction persisted 8-24 hours after allergen on both treatment days. Airway responsiveness to histamine was not significantly attenuated at 24 hours. CONCLUSION: Blocking Cys LT1 receptors for 8 hours attenuated the early and late responses but did not interrupt the cascade of events leading to subsequent allergen-induced airway obstruction and hyperreactivity.

Adult↗
PubMed1996

Human T-cell lymphotropic virus type I infection in Barbados: results of a 20-year follow-up study.

Forty-one human T-cell lymphotropic virus type I (HTLV-1)-seropositive individuals were identified among 1,012 subjects with stored serum samples from a health and seroepidemiological survey conducted in Barbados in 1972. These 41 subjects plus 79 HTLV-1 seronegative household members were targeted in a follow-up study 20 years later. Sixteen seropositive subjects and 22 seronegative subjects were interviewed, examined, and phlebotomized. There were no changes in HTLV-1 serostatus between the 1972 and follow-up serum samples. Three (19%) of the seropositive subjects had HTLV-1-associated disorders: two with dermatitis and one with "smoldering" adult T-cell leukemia. Neurologic and immunologic function was similar in HTLV-1-seropositive and HTLV-1-seronegative subjects. HTLV-1 antibodies persist over many years, and the risk for seroconversion of household contacts is low.

Adolescent↗
PubMed1996

Protection of MN-rgp120-immunized chimpanzees from heterologous infection with a primary isolate of human immunodeficiency virus type 1.

Three chimpanzees immunized with recombinant gp120 from human immunodeficiency virus type 1 (HIV-1) strain MN and 1 control animal were challenged intravenously with a primary isolate of HIV-1SF2. Viral infection was detected in the control animal by viral culture, polymerase chain reaction, and multiple serologic assays beginning 2 weeks after infection. Markers of HIV-1 infection were not detected in any of the gp120-vaccinated animals during 12 months of follow-up. Antisera from the gp120-immunized chimpanzees were unable to neutralize the challenge virus cultured in peripheral blood mononuclear cells (PBMC). These studies demonstrate that immunization with recombinant gp120 derived from a T cell-adapted isolate prevented infection by a heterologous primary isolate of HIV-1. The results suggest that in vitro virus neutralization assays utilizing primary isolates cultured in PBMC may be imperfect indicators of protection in vivo.

AIDS Vaccines↗
PubMed1995

Evolution of the cryptic FMR1 CGG repeat.

We have sequenced the 5' untranslated region of the orthologous FMR1 gene from 44 species of mammals. The CGG repeat is present in each species, suggesting conservation of the repeat over 150 million years of mammalian radiation. Most mammals possess small contiguous repeats (mean number of repeats = 8.0 +/- 0.8), but in primates, the repeats are larger (mean = 20.0 +/- 2.3) and more highly interrupted. Parsimony analysis predicts that enlargement of the FMR1 CGG repeat beyond 20 triplets has occurred in three different primate lineages. In man and gorilla, AGG interruptions occur with higher-order periodicity, suggesting that historical enlargement has involved incremental and vectorial addition of larger arrays demarcated by an interruption. Our data suggest that replication slippage and unequal crossing over have been operative during the evolution of this repeat.

Animals↗
PubMed1991

Mammalian hexokinase 1: evolutionary conservation and structure to function analysis.

We have amplified and sequenced the complete coding region of bovine hexokinase isoenzyme 1 (HK1) from brain RNA with PCR primers selected for sequence conservation. The sequence information was analyzed to evaluate the evolutionary and structure-function relationships among the mammalian and yeast HK isoenzymes. Structure to function analysis identified an unduplicated, invariant N-terminal domain involved in HK1 outer mitochondrial membrane targeting, as well as putative carbohydrate and nucleotide-binding sites in the regulatory and catalytic halves of HK1 essential to enzyme function. The ATP-binding site in the catalytic half of the HK1 protein resembles nucleotide-binding regions from protein kinases, with the single amino acid replacement (lysine to glutamate) in the ATP-binding site of the amino half explaining the loss of HK1 catalytic function in the regulatory domain. Sequence comparisons suggest that the 50-kDa mammalian and yeast glucokinases arose separately in evolution. In addition to providing valuable phylogenetic and structure-function insights, this work provides an efficient strategy for rapid cloning and sequencing of the coding regions for other HKs and related proteins.

Amino Acid Sequence↗
PubMed1987

Burnt out cases?

Explore the source record for details and available documents.

Burnout, Professional↗
PubMed1985

Genetic and physical studies of a portion of the white locus participating in transcriptional regulation and in synapsis-dependent interactions in Drosophila adult tissues.

We have identified and sequenced the portion of the white locus affected by an idiosyncratic set of white mutant alleles (the wsp alleles). The affected white locus portion (wsp region) extends from ca. 590 base pairs (bp) to ca. 1270 bp 5' to the apparent start site for the major white transcription unit. Based on the properties of these mutant alleles, we infer the existence of two distinct cis-acting regulatory elements in the wsp region and a third element mapping 3' to this region (3' to position ca. -670). Our analysis allows us to define the apparent position of one of the two wsp region elements with substantial precision. Examination of the DNA sequences in this region suggests that it is functionally similar to the enhancers identified in vertebrates. This same element participates in synapsis-dependent genetic interactions, suggesting a largely unexpected relationship between enhancer-like, cis-acting genetic elements and the genetic elements responsible for the synapsis-dependent genetic interactions in trans revealed by the existence of transvection effects. Our results further suggest that a presumptive regulatory locus (suppressor-of-white-spotted) regulates white transcription in adult tissues and is not involved in regulating white expression in larvae. We discuss the regulation of white expression in light of our studies. We also demonstrate unusual structures for an X-ray-induced deletion and a spontaneous deletion.

Alleles↗
PubMed1985

A detailed developmental and structural study of the transcriptional effects of insertion of the Copia transposon into the white locus of Drosophila melanogaster.

The copia insertion responsible for the wa mutation is 3' to the white promotor and in the same transcriptional orientation as white. First, we have analyzed the effects of the wa copia insertion on levels of polyadenylated white transcripts and find large, developmentally programmed effects. Second, we have isolated and sequenced an LTR-excision event involving the copia insertion at wa. This represents the first documented case of an LTR-excision event in Drosophila. This single copia LTR has developmentally programmed effects on white transcript levels qualitatively similar to the intact copia element. Third, we have characterized the structures of white transcripts from wa. We find polyadenylated white transcripts apparently having 3' termini in or near the 3' LTR of the wa copia insertion, as has been reported in limited studies of wa transcription in adults by others. These earlier studies also revealed wa transcripts apparently corresponding to polyadenylated terminus formation in the 5' LTR of the copia transposon; however, our more detailed studies reveal that these transcripts probably have other origins and that little, if any, polyadenylated terminus formation for white transcripts occurs in the 5' LTR of the wa copia insertion. Moreover, we find no polyadenylated terminus formation for white transcripts occurring in the single LTR of the wa LTR-excision product. Fourth, we find that each of three mutant alleles at su(wa) produces elevated levels of several classes of RNAs apparently corresponding to transcriptional readthrough of the wa copia transposon. Elevated levels of one presumptive readthrough transcript were observed previously in one su(wa) mutant strain. Fifth, we have confirmed the existence of a transcript initiated in the 3' LTR of the wa copia insertion and find the levels of this transcript to be strongly influenced by developmental stage and genetic background. Lastly, we have analyzed white transcripts produced by the whd81b11 allele, which carries an insertion of copia in the opposite transcriptional orientation and in a different position than the wa copia insertion. In contrast to the wa copia insertion allele, the whd81b11 allele produces polyadenylated white transcript levels very similar to the w+ case at the stages examined. Moreover, the whd81b11 copia element apparently produced polyadenylated terminus formation in white transcripts and we observe no effect of the allelic state of su(wa) on apparent readthrough of this stop site.(ABSTRACT TRUNCATED AT 400 WORDS)

Alleles↗
PubMed1983

Distribution of insertion element IS1 in natural isolates of Escherichia coli.

Total DNAs from twelve natural isolates of Escherichia coli from animals and humans were examined by hybridization with a probe for IS1. Considerable variation in copy number was found. In the case of two strains isolated from the same individual, one strain contained no copies of IS1 and the other, much greater than 30. Evidence was also obtained for the existence of IS1-like elements (iso-IS1s) of greater than 15% sequence divergence relative to the IS1 from antibiotic resistance plasmid R100.

Animals↗